Search Results (171)

Heterocyclic compounds are a common subject in the field of medicinal chemistry due to their numerous pharmaceutical applications. Among these, nitrogen- and oxygen-containing five-membered heterocyclic rings, namely oxazole and isoxazole, are particularly significant, exhibiting a broad spectrum of biological activities. Molecular hybridization, the process that enables the fusion of bioactive scaffolds, is a powerful strategy for the development of novel compounds characterized by enhanced or multitarget activities. This review focuses on hybrids incorporating linked oxazole and/or isoxazole moieties (i.e., isoxazole–oxazole and isoxazole–isoxazole hybrids), drawing upon peer-reviewed research articles and international patents from 1995 to the end of 2024. The overview systematically presents the diverse biological activities reported for the isoxazole–(iso)oxazole hybrids, including anticancer, antibacterial, antitubercular, anti-inflammatory, and antidepressant effects, alongside their corresponding chemical structures. Our analysis of the literature highlights the structural versatility and therapeutic potential of this important class of heterocyclic hybrids. Full article

Background/Objectives: In vitro, vancomycin (VAN) and tetrahydrolipstatin (THL) together have been shown to synergistically inhibit Mycobacterium tuberculosis (Mtb), the world’s most infectious killer. The poor oral bioavailability of VAN and THL and predominant tropism of Mtb infection to the lungs and alveolar macrophages make pulmonary administration highly attractive. This study aimed to develop and assess the efficacy of dry powders for inhalation of VAN microparticles embedded with THL. Methods: The dry powders produced by spray-drying, with or without hydrogenated castor oil (HCO), were characterized for their physicochemical properties among others by HPLC-DAD. The fast-screening impactor was used to determine powder aerodynamic properties, and VAN and THL releases were established from the paddle over disk method. Biological activities were assessed in a new M. bovis-infected macrophage model and in Mtb-infected mice. Results and Discussion: The addition of 25% HCO enables co-deposition (fine particle dose) at the desired weight ratio and co-releasing of VAN and THL in aqueous media. Microparticles with 0% to 50% HCO drastically reduced cytoplasmic Mycobacterium bovis survival (99.9% to 62.5%, respectively), with higher efficacy at low HCO concentration. Consequently, VAN/THL with or without 25% HCO was evaluated in Mtb-infected mice. Although no decrease in Mtb lung burden was observed after two weeks of administration, the endotracheal administration of VAN 500 mg/kg and THL 50 mg/kg with 25% HCO administrated three times during five days concomitantly with daily oral rifampicin (10 mg/kg) demonstrated 2-fold bacterial burden reduction compared to the group treated with RIF alone. Conclusions: HCO was crucial for obtaining a fine particle dose at the synergistic weight ratio (VAN/THL 10:1) and for releasing both drugs in aqueous media. With oral administration of the first-line rifampicin, the dry powder VAN/THL/25% HCO was able to exert a potential anti-tubercular effect in vivo in Mtb-infected mice after five days. Full article

Mycobacterium tuberculosis, the infectious agent behind tuberculosis (TB), underscores the significance of targeting enzymes such as arabinosyltransferases in drug development efforts. Benzothiozinone derivatives, which have been assessed for their effectiveness against TB, present a promising avenue for treatment. Utilizing a high virtual screening quantitative structure–activity relationship (QSAR-VS), a set of forty Benzothiozinone (C1–C40) compounds were investigated to build a robust model with satisfactory performance metrics (R² = 0.82, R²_adj = 0.78, N_test = 10, R²_test = 0.70). This model enabled the creation of databases containing new derivatives for screening drug-like properties and predicting MIC activity in TB treatment. The best-scoring compounds were screened by molecular docking with Mycobacterium tuberculosis kinases A and B (PDB code: 6B2P) and validated by molecular dynamics simulations to elucidate the most stable drug–protein interactions. Additionally, the MM-PBSA analysis shows that the strongest binding occurs in complexes X3, X4, and X6 with ΔG_bind values of −8.2, −15.3, and −12.0 kcal/mol, respectively. Our in silico study aims to prospect these new anti-tubercular drugs and their potential development through perspective in vitro and in vivo assays. Full article

Tuberculosis (TB) remains one of the leading causes of mortality worldwide, exacerbated by the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis strains. In the pursuit of novel therapeutic strategies, thiazolidin-4-one derivatives have gained significant attention due to their structural diversity and broad-spectrum biological activities. This review provides a comprehensive summary of recent advances (2021–present) in the synthesis, structure–activity relationship (SAR), and mechanisms of action of thiazolidin-4-one derivatives as promising antitubercular agents. A detailed discussion of synthetic pathways is presented, including classical and multi-component reactions leading to various subclasses such as thiazolidine-2,4-diones, rhodanines, and pseudothiohydantoins. The SAR analysis highlights key functional groups that enhance antimycobacterial activity, such as halogen substitutions and heterocyclic linkers, while molecular docking and in vitro studies elucidate interactions with key Mtb targets including InhA, MmpL3, and DNA gyrase. Several compounds demonstrate potent inhibitory effects with MIC values lower than or comparable to first-line TB drugs, alongside favorable cytotoxicity profiles. These findings underscore the potential of thiazolidin-4-one scaffolds as a valuable platform for the development of next-generation antitubercular therapeutics. Full article

This current review study covers the applications of vetiver essential oil (VEO) in phytoremediation, emphasizing its remedial capabilities in the cleaning of environmental pollutants like pesticides, fertilizers, fungicides, herbicides, heavy metals, dyes, and other industrial wastes such as chemical, mining, pharmaceutical, and other radioactive wastes. The review also emphasizes the pharmacological potential of vetiver essential oil for different applications, such as antioxidant, anti-inflammatory, antifungal, antibacterial, antitubercular, antihyperglycemic, antidepressant, hepatoprotective, and nephroprotective uses. The commercial potential of vetiver essential oil in diverse sectors, including global perspectives, is also illustrated along with demand scenarios in different sectors like food, beverage, fragrance, cosmetic and aromatherapy, hygiene, and pharmaceutical sectors. The main constituents of vetiver oil, their relative proportion, and the key findings of pharmacological studies performed using VEOs or their constituents are also summarized in this review article, with special emphasis on activity against phytopathogens. Full article

In 2022, the World Health Organization reported that tuberculosis (TB) was the second leading cause of death globally from a single infectious agent following COVID-19. The development of new antitubercular agents with novel mechanisms of action for use in complex TB therapy is considered a key approach to combating TB. In this study, we examined the gene expression profile of M. smegmatis when exposed to a promising antituberculosis agent, quinoxaline 1,4-dioxide (QdNO) 7-chloro-2-(ethoxycarbonyl)-3-methyl-6-(piperazin-1-yl)quinoxaline-1,4-dioxide-1 (LCTA-3368). We investigated how the bacterial response changed with different minimum inhibitory concentrations (MIC) (1/4 × MIC, 1/2 × MIC, and 1 × MIC) and durations (30 min and 90 min) of treatment with the drug. Our analysis revealed significant upregulation in genes involved in DNA repair and replication processes, as well as changes in the expression of 95 genes encoding proteins with oxidoreductase activity. We additionally showed that the concentration of reactive oxygen species increases in a dose-dependent manner upon exposure of M. smegmatis to LCTA-3368. These findings support the proposed mechanism of antibacterial action of QdNOs, which is associated with the formation of free radicals leading to DNA damage. Full article

Background/Objectives: Compounds derived from pyrimido-diazepine have shown selective inhibition of the susceptible Mycobacterium tuberculosis strain H37Rv. However, there is a need for studies that evaluate the activity of these compounds against multidrug-resistant strains and clinical isolates. This study aims to evaluate the antitubercular potential of FTSD2 against drug-resistant strains of M. tuberculosis. Methods: The compound 4-(2,4-diamino-8-(4-methoxyphenyl)-8,9-dihydro-7H-pyrimido[4,5-b][1,4]diazepin-6-yl)-N-(2-(4-(dimethylamino)-6-(4-fluorophenyl)amino-1,3,5-triazin-2-yl)amino)ethyl)benzenesulfonamide (FTSD2) was tested against drug-resistant M. tuberculosis strains at minimal inhibitory and bactericidal concentrations (MIC and MBC). Kill curve assays were performed to assess bactericidal activity, and cytotoxicity was evaluated in human monocyte-derived macrophages and the RAW 264.7 murine macrophage cell line. Intracellular death assays, specifically macrophage infection assays, were also conducted to evaluate the effect of FTSD2 on intracellular M. tuberculosis growth. Results: FTSD2 inhibited the growth of drug-resistant M. tuberculosis at MIC and MBC values between 0.5 and 1 mg/L. Kill curve assays demonstrated concentration-dependent bactericidal activity. No cytotoxicity was observed in macrophages at concentrations below 64 mg/L. Additionally, FTSD2 significantly suppressed intracellular M. tuberculosis growth after 192 h. FTSD2 did not inhibit the growth of nontuberculous mycobacteria, including M. avium, M. abscessus, M. fortuitum, M. chelonae, and M. smegmatis at 50 mg/L. Conclusions: FTSD2 exhibits strong potential as a leading compound for the development of new antitubercular drugs, with selective activity against M. tuberculosis and minimal cytotoxic effects on macrophages. Further studies are needed to explore its mechanisms of action and therapeutic potential. Full article

Caulerpin, a bis-indole alkaloid isolated from Caulerpa racemosa, has several documented pharmacological activities, including antineoplastic and antiviral properties. This study aimed to evaluate the anti-inflammatory and anti-tubercular potentials of caulerpin and its analogues in RAW 264.7 macrophages infected with Mycobacterium spp. Additionally, we evaluated cytokine production and NLRP3 expression in this infection model. Toxicity tests were performed using Vero E6 and HepG2 cell lines and Artemia salina. Pre-incubation of RAW 264.7 cells with caulerpin and its analogues decreased internalized M. smegmatis and M. tuberculosis H37Ra. Furthermore, treatment of M. smegmatis-infected macrophages with caulerpin and its analogues reduced bacterial loads. Caulerpin reduced the CFU count of internalized bacilli in the M. tuberculosis H37Ra infection model. In addition, caulerpin and its diethyl derivative were notably found to modulate IL-1β and TNF-α production in the M. smegmatis infection model after quantifying pro-inflammatory cytokines and NLRP3. Caulerpin and its derivates did not affect the viability of Vero E6 and HepG2 cell lines or nauplii survival in toxicity studies. These findings demonstrate that caulerpin and its analogues exhibit anti-inflammatory activity against Mycobacterium spp. infection in RAW 264.7 macrophages and show promising potential for further efficacy and safety evaluation. Full article

Selene-ethylenelacticamide derivatives have been suggested as promising scaffolds with leishmanicidal activity. In this work, we demonstrated, for the first time, the effectiveness of selene-ethylenelacticamide derivatives against mycobacteria. Firstly, selene-ethylenelacticamides inhibited the growth of laboratory strains of Mycobacterium tuberculosis with MIC values ranging from 10 to 20 µM. Importantly, three derivatives were active against two multi-drug-resistant clinical isolates of M. tuberculosis with MIC values similar to pan-sensitive strains. In addition, NC31 and NC34 displayed an improved activity compared to the group treated with isoniazid in the six-week nutrient-starved M. tuberculosis cultures. Moreover, in toxicity studies, NC34 did not significantly affect the viability of both Vero E6 and HepG2 cell lines. NC34 did not affect Artemia salina nauplii survival at concentrations lower than 100 µM. Importantly, NC34 displayed a synergistic effect when combined with rifampicin. Molecular docking simulations were used to evaluate Mycobacterium tuberculosis DprE1 and dihydrofolate reductase enzymes as putative targets of selene-ethylenelacticamides, mechanisms that could contribute to the antitubercular activity. Our findings reveal that NC34 may represent a hit for further drug optimization and for future preclinical development as a new anti-mycobacterial agent, especially in cases of resistant and/or dormant forms of tuberculosis. Full article

The synthetic approach based on a sequence of Buchwald–Hartwig cross-coupling and annulation through intramolecular oxidative cyclodehydrogenation has been used for the construction of novel 4-alkyl-4H-thieno[2′,3′:4,5]pyrrolo[2,3-b]quinoxaline derivatives. For the first time, these polycyclic compounds were evaluated for antimycobacterial activity, including extensively drug-resistant strains. A reasonable bacteriostatic effect against Mycobacterium tuberculosis H₃₇Rv was demonstrated. A plausible mechanism for antimycobacterial activity of heterocyclic analogues of indolo[2,3-b]quinoxalines has been advanced on the basis of their molecular docking data. Full article

Background: Recently, pyrido[2,3-d] pyrimidine, triazolopyrimidine, thiazolopyrimidine, quinoline, and pyrazole derivatives have gained attention due to their diverse biological activities, including antimicrobial, antioxidant, antitubercular, antitumor, anti-inflammatory, and antiviral effects. Objective: The synthesis of new heterocyclic compounds including 5-quinoline-pyrido[2,3-d] pyrimidinone (1–2, 4, 6–7), 6-quinoline-pyrido[2,3-d]thiazolo[3,2-a]pyrimidinone (3, 5, 8–10), 1,2,4-triazole-6-quinoline-pyrido[2,3-d]thiazolo[3,2-a]pyrimidinone (11–13), and pyrido[2,3-d]thiazolo[3,2-a]pyrimidine-ethyl-(pyridine)-9-thiaazabenzo[cd]azulenone (14) derivatives was performed with high yields while evaluating antimicrobial activities. Methods: A new series of quinoline-pyrido[2,3-d]thiazolo[3,2-a]pyrimidine derivatives were prepared using a modern style and advanced technology, resulting in high yields of these new compounds. Various reagents were utilized, specifically tailored to the production needs of each compound, through reactions that included alkylation, addition, condensation, acylation, the formation of Schiff bases, and intramolecular cyclization. Results: The chemical structures of the new compounds were determined using spectroscopy analyses, including IR, NMR, and MS, achieving good yields ranging from 68% to 90% under mild conditions in a regular system. All compounds were tested for in vitro antimicrobial activity and compared to standard drugs, specifically cefotaxime sodium and nystatin. The results showed that compounds 10 to 14 exhibited excellent antimicrobial activity, with a minimum inhibitory concentration (MIC) of 1 to 5 µmol/mL, compared to that of the standard drugs, which had MIC values of 1 to 3 µmol/mL. Furthermore, molecular docking studies were conducted to explore the interactions of specific compounds with antimicrobial target proteins. The findings revealed that compounds 10 to 14 displayed significant binding energies, with ΔG values ranging from −7.20 to −11.70 kcal/mol, indicating effective binding to the active sites of antimicrobial protein receptors. Conclusions: The SAR study confirmed a relationship between antimicrobial activity and the tested compounds. Molecular docking demonstrated that compounds 10, 11, 12, 13, and 14 exhibited significant binding energy, effectively interacting with the active sites of antimicrobial protein receptors. This consistent finding supports that these new compounds’ practical and theoretical studies align regarding their antimicrobial activity. Full article

Background/Objectives: Loading of natural products into poly-(lactide-co-glycolic) acid (PLGA) nanoparticles as drug delivery systems for the treatment of diseases, such as tuberculosis (TB), has been widely explored. The current study investigated the use of PLGA nanoparticles with 7-methyljuglone (7-MJ), an active pure compound, isolated from the roots of Euclea natalensis A. DC. Methods: 7-MJ as well as its respective PLGA nanoparticles were tested for their antimycobacterial activity against Mycobacterium smegmatis (M. smegmatis), drug-susceptible Mycobacterium tuberculosis (M. tuberculosis) (H37Rv), and multi-drug-resistant M. tuberculosis (MDR11). The cytotoxicity of 7-MJ as well as its respective PLGA nanoparticles were tested for their cytotoxic effect against differentiated human histiocytic lymphoma (U937) cells. Engulfment studies were also conducted to determine whether the PLGA nanoparticles are taken up by differentiated U937 cells. Results: 7-MJ has been shown to have a minimum inhibitory concentration (MIC) value of 1.6 µg/mL against M. smegmatis and multi-drug-resistant M. tuberculosis and 0.4 µg/mL against drug-susceptible M. tuberculosis. Whilst promising, 7-MJ was associated with cytotoxicity, with a fifty percent inhibition concentration (IC₅₀) of 3.25 µg/mL on differentiated U937 cells. In order to lower the cytotoxic potential, 7-MJ was loaded into PLGA nanoparticles. The 7-MJ PLGA nanoparticles showed an 80-fold decrease in cytotoxic activity compared to free 7-MJ, and the loaded nanoparticles were successfully taken up by differentiated macrophage-like U937 cells. Conclusions: The results of this study suggested the possibility of improved delivery during TB therapy via the use of PLGA nanoparticles. Full article

Background and Objectives: A novel antitubercular cyclic peptide, Cyclo(1,6)-Ac-CLYHFC-NH₂, was designed to bind at the rifampicin (RIF) binding site on the RNA polymerase (RNAP) of Mycobacterium tuberculosis (MTB). This peptide inhibits RNA elongation in the MTB transcription initiation assay in the nanomolar range, which can halt the MTB transcription initiation complex, similar to RIF. Therefore, determining the solution conformation of this peptide is useful in improving the peptide’s binding affinity to the RNAP. Methods: Here, the solution structure of Cyclo(1,6)-Ac-CLYHFC-NH₂ was determined by two-dimensional (2D) NMR experiments and NMR-restrained molecular dynamic (MD) simulations. Results: All protons of Cyclo(1,6)-Ac-CLYHFC-NH₂ were assigned using TOCSY and NOE NMR spectroscopy. The NOE cross-peak intensities were used to calculate interproton distances within the peptide. The J_NH-HCα coupling constants were used to determine the possible Phi angles within the peptide. The interproton distances and calculated Phi angles from NMR were used in NMR-restrained MD simulations. The NOE spectra showed NH-to-NH cross-peaks at Leu2-to-Tyr3 and Tyr3-to-His4, indicating a βI-turn formation at the Cys1-Leu2-Tyr3-His4 sequence. Conclusions: The NMR-restrained MD simulations showed several low-energy conformations that were congruent with the NMR data. Finally, the conformation of this peptide will be used to design derivatives that can better inhibit RNAP activity. Full article

Antimicrobial chemotherapeutic failure as a result of pathogenic resistance stain is great concern across the globe, there is need to search for an effective antimicrobial agent from synthetic sources to overcome emergent of microbial resistant in clinical practice. The phenylhydrazone derivatives were scientifically found to have wide application in the field of drug discovery due to their anticancer, anti-tubercular, antibacterial, and antifungal activities. The (E)-Substituted-N-(phenylhydrazones) derivatives were obtained by a condensation reaction between substituted acetophenone and substituted phenyl hydrazine through a one-step reaction, resulting of five (5) novel compounds such as HS1 (E)-1-(1-(4-bromophenyl)ethylidene)-2-(2,4-dinitrophenyl)hydrazine), HS2(E)-1-(1-(4-bromophenyl)ethylidene)-2-(4-nitrophenyl)hydrazine), HS3(E)-1-(4-nitrophenyl)-2-(1-(3-nitrophenyl)ethylidene)hydrazine), HS4(E)-1-(2,4-dinitrophenyl)-2-(1-(3-nitrophenyl)ethylidene)hydrazine), and HS5 (E)-1-(1-(3-nitrophenyl)ethylidene)-2-phenylhydrazine) and the in-silico prediction of physicochemical properties were found within Lipinski’s rule of five and the synthesized compounds were established by structurally elucidations on the basis of FTIR, 1D and 2D NMR spectral analysis and the newly synthesized compounds were then subjected to antimicrobial assessment for an in vitro test evaluation using the inhibition zone technique, minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), and minimum fungicidal concentration (MFC). Full article

A focussed library of pyridyl and 2-hydroxyphenyl chalcones were synthesized and tested for growth inhibitory activity against Mycobacterium tuberculosis H37Rv, and normal and cancer breast cell lines. Pyridyl chalcones bearing lipophilic A-ring, e.g., dichloro-phenyl-(14), pyrene-1-yl (20)- and biphenyl-4-yl (21) moieties were found to be the most potent of the series inhibiting the growth of M. tuberculosis H37Rv with IC₉₀ values ranging from 8.9–28 µM. Aryl chalcones containing a 3-methoxyphenyl A-ring and either p-Br-phenyl (25) or p-Cl-phenyl (26) B-rings showed an IC₉₀ value of 28 µM. Aryl-chalcones were generally less toxic to HepG2 cells compared to pyridyl-chalcones. Dose-dependent antiproliferative activity against MDA468 cells was observed for trimethoxy-phenyl (16) and anthracene-9-yl (19) pyridyl-chalcones with IC₅₀ values of 0.7 and 0.3 µM, respectively. Docking studies revealed that chalone 20 was predicted to bind to the M. tuberculosis protein tyrosine phosphatases B (PtpB) with higher affinity compared to a previously reported PtpB inhibitor. Full article